Discussion
ETP- ALL has been characterised by chemo-refractoriness and bad disease
biology.
High percentage of persistent minimal residual disease and poor overall
survival has been reported in ETP ALL patients treated with GRAALL 2003
and GRAALL 2005 protocol. However, response adapted treatment
stratification and use of allogeneic stem cell transplant in CR1 has
been shown to abrogate the negative effects of chemo-resistance in ETP
ALL [5]. Patients with ETP ALL have low rates of CR with standard
chemotherapy. In a small series from India only 1 of 6 patients of ETP-
ALL could achieve complete remission after initial chemotherapy [6].
Novel therapeutic agents studied in ETP ALL include dasatinib (patient
with NUP214-ABL1 aberration), ruxolitinib (JAK/STAT pathway),
daratumumab (anti CD38 antibody), gemtuzumab ozagamycin(anti CD 33
antibody conjugate) and venetoclax (BCL-2 inhibitor)[7]. Table 1
summarises the reports of venetoclax use in ETP ALL [8-10]. In a
study from MD Anderson Cancer Center, 13 patients of relapsed refractory
T cell ALL which included 5 patients of ETP ALL were treated with
venetoclax in combination with various chemotherapy regimens [11].
The median dose given was 200 mg with a total duration of 21 days in
combination with HyperCVAD, fludarabine+ cytarabine + idarubicin,
decitabine, nelarabine and asparaginase. Prolonged cytopenias were
observed with dose of 400 mg/day or duration of therapy >
14 days. 60% of patients achieved complete remission. No association
between bone marrow response and dose was observed. The median OS was
7.7 months. Only 1 ETP ALL patient achieved MRD negativity. Only 2
patients were alive at 1 year and both had ETP ALL. Duration of
remission achieved with venetoclax was short lived. In our study we used
100mg on day 1, 200 mg on day 2, 300 mg on day 3 and 100 mg with oral
posaconazole from day 4 to day 7 onwards in combination with BFM 95
regimen. Both patients attained complete remission after 1 course of
venetoclax combination chemotherapy. One patient achieved MRD negativity
after 1 course of venetoclax and the other patient achieved MRD
negativity after 2nd course of venetoclax. In a study
by El-Cheikh J et al, 3 patients of relapsed refractory T cell ALL were
treated with venetoclax and BFM based therapy [12] . 2 patients
achieved CR.
Combinations of venetoclax with other chemotherapeutic agents have been
studied in relapsed refractory ALL. Navitoclax is a novel inhibitor of
BCL-XL and in combination with Venetoclax has shown synergistic effect
in phase 1 study in patients with relapsed/refractory B and T cell acute
lymphoblastic leukemia [13]. The overall rate of combined complete
response, CR with incomplete marrow recovery or incomplete platelet
recovery was 49%. Responses of combination therapy of venetoclax(800 mg
followed by 400 mg with azoles)with decitabine in relapsed T cell ALL
post allogeneic stem cell transplant have also been described[14,
15]. Patient had also achieved MRD negativity. Individualized therapy
based on drug response profiling of leukemia cells with venetoclax and
bortezomib was done in 3 patients of relapsed refractory ETP ALL. 1
patient achieved CR and 2 PR. All patients underwent transplant and
achieved remission [16]. Currently a phase I/II study is undergoing
in MDACC of venetoclax in combination with low dose chemotherapy in
relapsed refractory T cell
ALL(NCT03808610). We
used a short low dose regimen with posaconazole which was well tolerated
and achieved good results in our patients.